Process for the preparation of methyl 4-[[3-(3,5-difluorophenyl)-5-vinyl-4h-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate

Abstract

The present invention relates to a novel process for preparing methyl 4-[[3-(3,5-difluorophenyl)-5-vinyl- 4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (I) in all its stereoisomeric forms, mixtures thereof and agrochemical acceptable salts thereof.

Description

[0001] Process for the preparation of methyl 4-[[3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5- carbonyl]amino]tetrahvdrofuran-2-carboxylate

[0002] The present invention relates to a novel process for preparing methyl 4-[[3-(3,5-difluorophenyl)-5-vinyl- 4H-isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (I) in all its stereoisomeric forms, mixtures thereof and agrochemical acceptable salts thereof

[0003] The synthesis of methyl 4-[[3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5- carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (I) has already been described in WO 2018 / 228985 Al. The process includes activation of the acid precursor via acid chloride formation. However, these steps are carried out in dichloromethane with excess of oxalyl chloride as chlorinating agent. Both, the solvent and the applied chlorinating agent are not suitable for large scale in terms of safety, environmental and economic aspects. In addition, the process also requires DMF as a catalyst which, in combination with commonly used chlorinating agents (e.g. thionyl chloride), would lead to the formation of side products with significant safety risk. Besides that, extended reaction and cycle times are required and would largely increase the cost of the process and might impact the stability of the formed acid chloride.

[0004] An object of the present invention is the provision of an efficient, cost-effective and lean process for preparing 4-[[3 -(3 ,5 -difluorophenyl)-5 -vinyl -4H-isoxazole-5 -carbonyl] amino]tetrahydro-furan-2- carboxylate of formula (I) in all its stereoisomeric forms and agrochemical acceptable salts thereof that can be used on industrial scale avoiding the above-mentioned disadvantages. Key for improving the synthesis is the optimization of the transformation of compound of formula (II) to compound of formula (HI)

[0005] The object is achieved by a process for preparing methyl 4-[[3-(3,5-difluorophenyl)-5-vinyl-4H- isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate (I) in all its stereoisomeric forms, mixtures thereof and agrochemical acceptable salts thereof

[0006] characterized in that compound of formula (II), 3 -(3 ,5 -difluorophenyl) -5 -vinyl -4H-isoxazole-5 - carboxylic acid or salts thereof react in a first step in the presence of SOCI2, phosgene or triphosgene and an additive to compound of formula (III), 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl chloride and in a second step, (III) is further converted in the presence of compound of formula (IV) or salts thereof to compound of the formula (I).

[0007] Salts of compound of formula (IV) that can be used according to the invention were disclosed in WO 2023 / 186692 and WO 2023 / 161204.

[0008] In a further embodiment the salts of compound of formula (IV) used according to the invention are: hydrochloride salts, hydrogensulfate or sulfate salts, methanesulfonate salts, trifluoromethanesulfonate salts or trifluoroacetate salts.

[0009] In a further preferred embodiment the salts of compound of formula (IV) used according to the invention are: hydrochloride salts.

[0010] Preferred is a process for preparing methyl(2R*,4R*)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H- isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (la) and agrochemical acceptable salts thereof existing in the form of two stereoisomers or their mixtures: Methyl(2R,4R)-4-[[(5S)-3-(3,5- difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl]-amino]tetrahydrofuran-2 -carboxylate of formula

[0011] (laa) and methyl (2S,4S)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5- carbonyl]amino]tetrahydrofuran-2 -carboxylate of formula (lab)

[0012] (laa) (lab) characterized in that compound of formula (Ila) or salts thereof reacts in a first step in the presence of SOCh, phosgene or triphosgene and an additive to compound of formula (Illa) and in a second step, (Illa) is further converted in the presence of compound of formula (IVaa) or (IVab) or salts or mixtures thereof

[0013] (IVaa) (IVab) to compound of the formula (laa) or (lab) or a mixture thereof.

[0014] In a further embodiment the salts used according to the invention are: hydrochloride salts, hydrogensulfate or sulfate salts, methanesulfonate salts, trifluoromethanesulfonate salts or trifluoroacetate salts.

[0015] In a further preferred embodiment the salts used according to the invention are: hydrochloride salts.

[0016] The present invention has the advantage, that the halogenation reaction is significantly accelerated by use of catalytic amounts of cheap and readily available additives including amine sources as well as organic and inorganic salts. In addition, the process could be further improved by significant reduction of required chlorinating agent, the use of technically more feasible solvents and enhancement of overall process robustness. In total, the present invention leads to large improvement of the environmental and economic footprint of the process by cycle time and input reduction as well as capacity increase.

[0017] Compound of formula (Ila) and its synthesis has already been described in WO 2018228985A1, WO 2023 / 099641 and WO 2024 / 038036.

[0018] Compound of formula (IVa), (IVaa) and (IVab) and mixtures thereof and their synthesis is known from e.g. WO 2023 / 161204. Elucidation of the processes and intermediates

[0019] Process for preparing 4-[[3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5- carbonyl]amino]tetrahydrofuran-2-carboxylate of formula (I), characterized in that compound of (II) reacts in a first step in the presence of chlorinating agent and an additive to compound of formula (III) and in a second step is further converted with a compound of formula (IV) or salts thereof in the presence of a base to compound of the formula (I):

[0020] Scheme 1: Chlorination

[0021] Scheme 2: Amide Formation

[0022] (HI) (IV) (I) Step 1

[0023] Reagents

[0024] In the process according to the invention 0.9 to 3.0, preferably 1.0 to 1.5 equivalents of a chlorinating agent, such as SOCk, phosgene or triphosgene, preferably SOCI2, were used.

[0025] Additives

[0026] In the process according to the invention an additive which has the function of a catalyst is used. Suitable additives are primary amines, secondary amines, tertiary amines, ammonium salts, iminium salts, pyridine derivatives, inorganic and organic salts (such as chloride salts), phosphonium salts, and dibutyl formamide. Preferably 0.005 to 0.3, more preferably 0.02 to 0.20 equivalents of the additive relating to compound of formula (II) were used.

[0027] In a preferred embodiment, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hydrogensulfate, tetrabutylphosphonium chloride, ammonium chloride, tetramethyl ammonium chloride, hexamethylguanidinium chloride, triethylamine, dimethylcylohexyl amine, triethylammonium chloride, dimethylcyclohexylammonium chloride, N-methylcyclohexyl amine, N-methylcyclohexylammonium chloride, cyclohexyl amine, cyclohexylammonium chloride, pyridine, pyridinium hydrochloride, Eschenmoser’s salt, potassium chloride, and dibutyl formamide were used.

[0028] In a very preferred embodiment, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylamine, dimethylcyclohexyl amine, dimethylcyclohexylammonium chloride and triethylammonium chloride were used.

[0029] Temperature range for the acid-chlorination (step 1)

[0030] The halogenation is usually performed in a temperature range from -10 °C to 75 °C, preferably -5 °C to 60 °C,

[0031] Solvent for the acid-chlorination (step 1)

[0032] Acid-chlorination is furthermore performed in the presence of a solvent or diluent, preferred solvents being toluene, xylenes, chlorobenzene, chloroform, dichloromethane, acetonitrile or mixtures of the above-mentioned solvents.

[0033] Step 2

[0034] Reagents In the process according to the invention 0.90 to 1.5, preferably 0.95 to 1.2 equivalents of compound (IV) were used

[0035] In the process according to the invention 1.80 to 2.5, preferably 1.9 to 2.3 equivalents of an organic base, such as tertiary amines or pyridine derivatives were used.

[0036] In a preferred embodiment, dimethylethylamine, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, dimethylcyclohexylamine, pyridine, picolines, 5 -ethyl -2 -methylpyridine or lutidine were used.

[0037] In a very preferred embodiment, triethylamine, tributylamine and dimethylcyclohexylamine were used.

[0038] The amide coupling is usually performed in a temperature range from -10 °C to 100 °C, preferably -5 °C to 80 °C.

[0039] Solvent for the amide synthesis

[0040] The amide synthesis is furthermore performed in the presence of a solvent or diluent, preferred solvents being toluene, chlorobenzene, xylenes, chloroform, dichloromethane, acetonitrile or mixtures of the above-mentioned solvents. In a preferred embodiment, step 2 is conducted in the same solvent as step 1.

[0041] The reaction according to the invention can be performed analogously for all isomeric forms or any mixtures thereof.

[0042] Examples

[0043] The present invention is elucidated in more detail by the examples that follow, without restriction of the invention thereto.

[0044] Measurement methods

[0045] The products were characterized by ’H spectroscopy and / or HPLC and / or MS (Liquid Chromatography Mass Spectrometry).

[0046] The NMR spectra were determined using a ECZL 400S NMR (JEOL 40 MHz NMR) or Bruker Avance Neo 600.

[0047] The product assay determination by quantitative HPLC was measured on an Agilent Technologies HP 1260 using Agilent XDB C18 column (1.8 pm) and acetonitrile, aqueous phosphoric acid gradient. Certified material of methyl (2RS,4RS)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5- carbonyl]amino]tetrahydrofuran-2 -carboxylate was used as references substance.

[0048] Step 1 Example Il-a: Preparation of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic chloride

[0049] Using solid 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid as reactant:

[0050] 7 g (1.0 eq., 26.3 mmol) of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid was dissolved in 19 mL of xylenes at 50 °C. Then 0.385 g tetrabutylammonium chloride (5 mol%, 1.31 mmol) was added to the mixture, followed by dropwise addition of 2. 1 mL (1.1 eq., 28.9 mmol) of SOCL preferably over 5 minutes. During the addition, a considerable amount of gas development was visible. The mixture continued to stir at 50 °C for 5 h, HPLC indicated full conversion to the desired product, and then excess SOCL was distilled out. The raw product in xylenes thus obtained was directly used in the next step without further purification.

[0051] Using technical solution of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid as reactant:

[0052] 35 g (1.0 eq., 27.6 mmol) of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid solution (20%) in toluene was heated at 50 °C. Then 0.396 g tetrabutylammonium chloride (5 mol%, 1.38 mmol) was added to the mixture, followed by dropwise addition of 2.6 mL (1.3 eq., 35.9 mmol) of SOCL preferably over 30 minutes. During the addition, a considerable amount of gas development was visible. The mixture continued to stir at 50 °C for 3 h, HPLC indicated full conversion to the desired product, and then excess of SOCL was distilled off. The raw product in toluene solution thus obtained was directly used to the next stage without further purification.

[0053] An analytical sample was generated by taking a small amount of crude reaction mixture which was dried under reduced pressure and yielding crude of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5- carboxylic chloride.

[0054] 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic chloride: ’H-NMR (600 MHz, CDCk): 5 7.20 - 7.14 (m, 2H), 6.85 (tt, J = 8.7, 2.3 Hz, 1H), 6.12 (dd, J = 17.2, 10.7 Hz, 1H), 5.53 (d, J = 17.2 Hz, 1H), 5.37 (d, J= 10.7 Hz, 1H), 3.92 (d, J= 17.0 Hz, 1H), 3.82 (s, 3H), 3.33 (d, J= 16.9 Hz, 1H) ppm.

[0055] The conversion of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic chloride was determined by converting it to corresponding methyl-ester product, methyl 3-(3,5-difluorophenyl)-5-vinyl-4H- isoxazole-5-carboxylate, due to the hydrolysis of the chloride-product into parent acid-substrate in presence of water. Complete analytical data of corresponding methyl ester product are provided below.

[0056] Methyl 3 -(3, 5 -difluorophenyl)-5 -vinyl -4H-isoxazole-5 -carboxylate: 'H NMR (600 MHz, CDCk): 5 7.20 - 7.14 (m, 2H), 6.85 (tt, J= 8.7, 2.3 Hz, 1H), 6.12 (dd, J= 17.2, 10.7 Hz, 1H), 5.53 (d, J= 17.2 Hz, 1H), 5.37 (d, J= 10.7 Hz, 1H), 3.92 (d, J= 17.0 Hz, 1H), 3.82 (s, 3H), 3.33 (d, J= 16.9 Hz, 1H) ppm.13C NMR (151 MHz, CDC13): 5 170.80, 163.99, 163.90, 162.33, 162.25, 154.68, 154.66, 154.64, 134.37, 132.01, 131.95, 131.88, 117.55, 109.98, 109.94, 109.84, 109.80, 106.02, 105.85, 105.68, 89.44, 53.45, 43.60 ppm.

[0057] 19F NMR (CDCh): 5 -108.4 ppm. LC-MS: [M+H]+= 268.4 m / z

[0058] In accordance with example Il-a (Step 1), the following examples have been prepared:

[0059] 11' Conversion of product was determined by formation of methyl ester of the corresponding acid which was done by quenching the crude acid chloride with MeOH.1:11Technical solution of 3-(3,5-difluorophenyl)-5-vinyl-4H- isoxazole-5-carboxylic acid was used as substrate.C)Reaction was carried out with phosgene as chlorinating agent instead SOCh.d)Reaction was carried out with triphosgene as chlorinating agent instead SOCI2.* DBF = N,N- dibutylformamide. ** DMCHA = N,N-dimethylcyclohexylamine. *** TEA = Triethylamine.

[0060] Step 2

[0061] Example 1-a: Preparation of methyl (2RS,4RS)-4-[[(5S)-3-(3,5-difluorophenyl)-5-vinyl-4H- isoxazole-5-carbonyl]amino]tetrahydrofuran-2-carboxylate To 339 g 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic chloride (example Il-a) as ca. 20% solution in toluene (0.25 mol, 1.0 eq), prepared according to step 1, 49,2 g methyl rac-(2S,4S)-4- aminotetrahydrofuran-2 -carboxylate hydrochloride (1.05 eq, containing 4% of rac-(2S,4R)-4- aminotetrahydrofuran-2 -carboxylate hydrochloride) are added at 20 °C. After heating the mixture to 50 °C, at this temperature, 70.7 g (2.2 eq) N,N-dimethylcyclohexylamine are added over 7 h. After full addition the suspension is further stirred at this temperature for at least 2 h. Then, the mixture is quenched by the addition of 125 g water, phases are separated, and the remaining organic phase is washed with aqueous carbonate solution at pH 8. Finally, the organic phase is dried by distillation and toluene is distilled off the mixture. The crude material is dissolved in 308 g 2-propanol at 60-70 °C, cooled to 50 °C followed by the addition of 26.8 g acetone. After cooling and seeding, the resulting suspension is further stirred at 5 °C and filtered. The filter cake is washed with 2-propanol twice and dried at 60 °C under vacuum. 73.6 g (86% purity, 66% yield, d.r. 42 : 57) of the product is obtained as a solid (Product contains 1.3 % trans-isomer) .

[0062] LC-MS: 3.92 min (381.126, M+l; minor isomer, trans), 4.95 min (381.126, M+l; major isomer, cis)

[0063] ' H-NMR (CDCT): 52.08 (m, 1H), 2.56 (m, 1H), 3.30 (dd, 1H), 3.81 (s, 3H), 3.88 (dd, 1H), 3.92 (m, 1H), 4.02 (dd, 1H), 4.56 (dd, 1H), 4.58 (m, 1H), 5.33 (dd, 1H), 5.52 (dd, 1H), 6.14 (dd, 1H), 6.88 (m, 1H), 7.17 (m, 2H), 7.44 (d, 1H) (Diastereomer 1) ppm; 2.03 (m, 1H), 2.52 (m, 1H), 3.29 (dd, 1H), 3.80 (s, 3H), 3.90 (dd, 1H), 3.94 (m, 1H), 4.04 (dd, 1H), 4.54 (dd, 1H), 4.61 (m, 1H), 5.34 (dd, 1H), 5.54 (dd, 1H), 6.14 (dd, 1H), 6.88 (m, 1H), 7.17 (m, 2H), 7.47 (d, 1H) (Diastereomer 2) ppm.

[0064] 13C-NMR (CDCh): 5 36.9, 44.2, 49.8, 52.6, 74.4, 76.2, 90.1, 105.9, 109.9, 117.0, 131.6, 134.8, 155.6, 163.0, 170.5, 173.2 (Diastereomer 1) ppm; 36.8, 44.1, 49.8, 52.6, 74.4, 76.2, 90.2, 105.9, 109.8, 117.2, 131.7, 134.6, 155.6, 163.0, 170.5, 173.1 (Diastereomer 2) ppm.

[0065] 19F-NMR (CDCh): 5 -108.7 (m, 2F) ppm.

Claims

1. Claims:

1. Process for preparing compound (III)characterized in that compound of formula (II) or salts thereofare chlorinatedin the presence of SOCI2, phosgene or triphosgene and an additive.

2. Process according to Claim 1, wherein compound of formula (III) is further converted in the presence of compound of formula (IV) or salts thereofto compound of the formula (I)in all its stereoisomeric forms, mixtures thereof and agrochemical acceptable salts thereof.

3. Process according to Claims 1, wherein compound of formula (Ila)is used for (II).

4. Process according to Claims 2, wherein compound of formula (Illa)is used for (III).

5. Process according to any of claims 1 to 4, wherein the reagent in step 1 is SOCE.

6. Process according to any of claims 1 to 5, wherein the additive in step 1 is tetrabutylammonium chloride, tetrabutylammonium bromide, triethylamine, dimethylcyclohexyl amine, dimethylcyclohexylammonium chloride or triethylammonium chloride.

7. Process according to any of claims 1 to 5, wherein the solvent is toluene or xylenes.

8. Compound of formula (II), 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acidor salts thereof.

9. Compound of formula (III), 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carbonyl chloride(HI).

10. Compound of formula (IV) or salts thereof

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